9-21974861-C-A

Variant names:

• chr9-21974861-C-A
• rs1800586
• ENST00000498124.1:c.-34G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The ENST00000498124.1(CDKN2A):​c.-34G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,509,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: CDKN2A ENST00000498124.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: -0.827

Genes affected

CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 9-21974861-C-A is Pathogenic according to our data. Variant chr9-21974861-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 182414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21974861-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.194-3653G>T		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
CDKN2A	NM_000077.5	c.-34G>T		upstream_gene_variant		ENST00000304494.10	NP_000068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.194-3653G>T		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000304494.10	c.-34G>T		upstream_gene_variant		1	NM_000077.5	ENSP00000307101.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000433 AC: 5 AN: 115386 Hom.: 0 AF XY: 0.0000474 AC XY: 3 AN XY: 63326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000778

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000656 AC: 89 AN: 1357220 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 35 AN XY: 668658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000175

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000748

Gnomad4 OTH exome AF: 0.0000711

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN2A: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Describes a nucleotide substitution 34 base pairs upstream of the ATG translational start site of the CDKN2A gene that creates an aberrant ATG translation initiation codon; Published functional studies demonstrate a damaging effect: decreases translation from the wild-type ATG and results in a truncated protein that significantly affects reporter activity (PMID: 9916806, 20093296); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 26557774, 26775776, 19523171, 16896043, 25780468, 9916806, 20093296, 26581427, 26681309, 26099287, 12072543, 26681312, 16397522, 16905682, 15146471, 28495237, 29263814, 28830827, 30067863, 30117292, 30113427, 31567591, 33077847, 32482799, 34598035, 17713569, 29922827) -

Feb 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A c.-34G>T variant has been reported in the published literature in functional studies that indicate this variant creates an out of frame translation initiation codon that results in a truncated protein and decreases translation from the wild-type start site. The variant also had a negative impact on transcriptional activity in a luciferase reporter assay (PMIDs: 9916806 (1999) and 20093296 (2010)). In addition, the variant has been reported in multiple individuals and families affected with familial melanoma (PMIDs: 16397522 (2006), 17713569 (2008), 19523171 (2009), 25780468 (2014), 26681309 (2016), 26775776 (2016), and 31567591 (2020)), and showed a strong co-segregation with disease (PMIDs: 9916806 (1999) and 10738302 (2000)). The frequency of this variant in the general population, 0.000075 (5/66812 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Mar 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A c.-34G>T variant (rs1800586; ClinVar ID: 182414) is reported in the literature in multiple individuals affected with melanoma and/or pancreatic cancer and has been demonstrated to co-segregate with disease in multiple families (Andreotti 2016, Ashton-Prolla 2008, Bran 2018, Liu 1999, Overbeek 2021, Taylor 2017). This variant is found in the general population with a low overall allele frequency of 0.004% (6/146,754 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the 5’ untranslated region of the CDKN2A gene and is predicted to create a novel initiation codon that results in a truncated protein (Liu 1999). Functional analysis in multiple cell lines suggests the variant is associated with significantly reduced expression from the canonical initiation codon (Liu 1999, Andreotti 2016, Bisio 2010). Based on available information, this variant is considered to be pathogenic. References: Andreotti V et al. The CDKN2A/p16(INK) (4a) 5'UTR sequence and translational regulation: impact of novel variants predisposing to melanoma. Pigment Cell Melanoma Res. 2016 Mar;29(2):210-21. PMID: 26581427. Ashton-Prolla P et al. Clinical and molecular characterization of patients at risk for hereditary melanoma in southern Brazil. J Invest Dermatol. 2008 Feb;128(2):421-5. PMID: 17713569. Bisio A et al. Functional analysis of CDKN2A/p16INK4a 5'-UTR variants predisposing to melanoma. Hum Mol Genet. 2010 Apr 15;19(8):1479-91. PMID: 20093296. Brand R et al. Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer. 2018 Sep 1;124(17):3520-3527. PMID: 30067863. Liu L et al. Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet. 1999 Jan;21(1):128-32. PMID: 9916806. Overbeek KA et al. Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants. J Med Genet. 2021 Apr;58(4):264-269. PMID: 32482799. Taylor NJ et al. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. J Invest Dermatol. 2017 Dec;137(12):2606-2612. PMID: 28830827. -

Melanoma-pancreatic cancer syndrome Pathogenic:2

May 03, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-34G>T pathogenic mutation is located in the 5' untranslated region (5'UTR) of the CDKN2A gene. This mutation results from a G to T substitution 34 nucleotides upstream from the first translated codon. This sequence alteration creates a potential AUG initiation codon at base -35 and translation initiation from this novel start site predicts a truncated protein with no homology to wild type (Liu L et al. Nat. Genet. 1999 Jan;21:128-32). Functional studies demonstrate that the c.-34G>T mutation severely reduces the reporter activity in every cell type tested (Bisio A et al. Hum. Mol. Genet. 2010 Apr;19:1479-91). This alteration was identified in an individual with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res. 2020 06;30:247-251). In addition, this alteration has been reported in numerous families with melanoma, pancreatic cancer, and/or atypical nevi, and has been shown to segregate with disease (Liu L et al. Nat. Genet. 1999 Jan;21:128-32; Berwick M et al. Cancer Epidemiol. Biomarkers Prev. 2006 Aug;15:1520-5; Florell SR et al. J. Invest. Dermatol. 2008 Aug;128:2122-5; Larre Borges A et al. Br. J. Dermatol. 2009 Sep;161:536-41; Harland M et al. Hered. Cancer Clin. Pract. 2014 Nov;12:20; Bruno W et al. J. Am. Acad. Dermatol. 2016 Feb;74:325-32; Puig S et al. Genet. Med. 2016 Jul;18:727-36; Taylor NJ et al. J. Invest. Dermatol. 2017 12;137(12):2606-2612; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Apr 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant is located in the 5' untranslated region of the CDKN2A gene (P16INK4A). A functional study has shown that this variant creates a new translation initiation AUG codon, and translation initiation from this novel site results in a truncated protein, while blocking wild-type protein expression (PMID: 9916806). This variant has been reported in over thirty individuals affected with melanoma (PMID: 9916806, 16397522, 17713569, 18025365, 19523171, 25023876, 25780468, 26581427, 26681309, 26775776, 29263814, 31567591) and has been shown to segregate with melanoma and pancreatic cancer in four different families (PMID: 9916806). This variant has been identified in 6/146754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Melanoma, cutaneous malignant, susceptibility to, 2 Pathogenic:1 Other:1

Aug 25, 2022

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 1999

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Melanoma and neural system tumor syndrome Pathogenic:1

Jan 31, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma;C0919267:Ovarian neoplasm Pathogenic:1

Oct 14, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PP1 strong -

CDKN2A-related disorder Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDKN2A c.-34G>T variant is located in the 5' untranslated region. This variant corresponds to a deep intronic position in the alternate transcript for this gene that encodes p14ARF (NM_058195.3:c.194-3653G>T). This variant has been reported in individuals with melanoma and segregated within families (Liu et al. 1999. PubMed ID: 9916806; Harland et al. 2000. PubMed ID: 10738302; Andreotti et al. 2016. PubMed ID: 26581427). It has also been reported in an individual with pancreatic adenocarcinoma (Brand et al. 2018. PubMed ID: 30067863). In vitro experimental studies indicate that this variant results in a novel alternative initiator that subsequently leads to decreased translation from the normal start site and ultimately a truncated protein (Liu et al. 1999. PubMed ID: 9916806). In addition, this variant significantly alters transcriptional activity as observed by in vitro reporter assay (Bisio et al. 2010. PubMed ID: 20093296). This variant is reported in 6 of ~147,000 alleles in gnomAD; however, the data quality is questionable and should be interpreted with caution. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182414/). This variant is interpreted as pathogenic. -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial melanoma Pathogenic:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the CDKN2A (p16INK4a) gene. It does not change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with familial melanoma (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). It is commonly reported in individuals of British ancestry (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). ClinVar contains an entry for this variant (Variation ID: 182414). Studies have shown that this variant alters CDKN2A (p16INK4a) gene expression (PMID: 9916806, 20093296). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800586; hg19: chr9-21974860; COSMIC: COSV58702359; COSMIC: COSV58702359;